Recent methodological advances in genomics and neuroscience have made it possible, for the first time, to determine how the human brain differs from that of other species. This research has revealed differences ranging from long-range neuronal connectivity to molecular changes, such as gene expression. Identifying these human-specific characteristics is vitally important for understanding common neurological and psychiatric diseases such as schizophrenia, autism, and Alzheimer's, diseases that have no definite counterparts in other primates and involve regions of the brain that underwent dramatic changes in size and internal organization in human evolution. However, the molecular mechanisms that underlie these diseases remain elusive. Our preliminary study of DNA methylation provides clues to these mechanisms, demonstrating that genes associated with neuropsychiatric disorders exhibit highly divergent DNA methylation patterns in human brains compared to non-human primate brains. Moreover, several human-specific gene co-expression networks that are strongly associated with neuropsychiatric disorders are enriched in genes that harbor human-specific DNA methylation signatures. In light of these observations, and of the emerging link between epigenomic markers and neuropsychiatric disorders, the systematic study of human epigenomic specializations promises to deepen our understanding of the molecular mechanisms that contribute to neuropsychiatric diseases and foster development of novel therapeutic interventions. The objectives of this project are to: (1) identify human-brain specific DNA methylation patterns; (2) elucidate the role of DNA methylation changes in the regulation of human-specific gene expression and co- expression networks; and (3) test the relevance of these epigenomic and transcriptomic changes in the context of neuropsychiatric diseases. We will examine two higher-order cortical regions from multiple human, chimpanzee, and macaque brains, drawing on the extensive collections of archival brain tissue available at the Yerkes National Primate Research Center. This comparative framework will enable us to pinpoint DNA methylation changes that accompanied changes in human brain structure and function. The link between human brain molecular specialization and human neuropsychiatric disorders will be verified by comparing control human brains to brains of schizophrenia patients, obtained from the Dallas Brain Collection (DBC) at UT Southwestern. The proposed studies of this multiple-PI and collaborator effort will leverage complementary and intersecting interests in epigenetics and evolution (Yi), comparative primate neurobiology (Preuss), and molecular neuroscience (Konopka). The application of our combined expertise to the analysis of the rich collection of DBC brain-disorder samples will promote discoveries of novel epigenetic mechanisms of neuropsychiatric disorders and provide the foundation for new insights and novel clinical approaches.